The compound 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (also referred to herein as “compound 1”), may be represented by the structure:
and is also known as palbociclib or PD-0332991. Compound 1 is a potent and selective inhibitor of CDK4 and CDK6.
Compound 1 and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2003/062236 and U.S. Pat. Nos. 6,936,612, 7,208,489 and 7,456,168, which describe the preparation of compound 1 as its hydrochloride salt. International Publication No. WO 2005/005426 and U.S. Pat. Nos. 7,345,171 and 7,863,278 describe preparation of the free base and various mono- and di-acid addition salts of compound 1, including polymorphic forms of the isethionate salt. A process for the preparation of compound 1 as a mono-isethionate salt is described in International Publication No. WO 2008/032157 and U.S. Pat. No. 7,781,583. The contents of each of the foregoing references are incorporated herein by reference in their entirety.
While compound 1 is a potent and selective CDK4/CDK6 inhibitor, its use as a free base presented challenges for pharmaceutical development. The free base provided by traditional salt break procedures, e.g., as in Example 4 of WO 2005/005426, was highly static prone and formed small primary particles, which agglomerated into large, hard agglomerates that were difficult to disperse by sieving and were unsuitable for further development. The present invention provides compound 1 free base having larger primary particle size that demonstrates improved physicochemical and manufacturability properties.